Papillary cystadenomas (benign cystic tumors) of the epididymis (structure in the male reproductive system) or broad ligament (structure in the female reproductive system)

Because Von Hippel-Lindau syndrome is hereditary, the risk of developing features associated with VHL may be passed from generation to generation in a family. However, the type and severity of Von Hippel-Lindau syndrome can vary widely between family members.

Von Hippel-Lindau syndrome is caused by alterations, also known as mutations, at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions cells require to perform different functions within our bodies.

In almost 100 percent of patients with Von Hippel-Lindau syndrome, the disorder develops as the result of alterations in a specific gene known as VHL, which is located on chromosome 3 at position p26-p25. VHL is the only gene known to be associated with Von Hippel-Lindau syndrome. The protein produced by the VHL gene acts as a “tumor suppressor," which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death. It also has a fundamental role in regulating the biological pathways involved with normal blood vessel growth.

With the exception of egg and sperm cells, each cell of the body normally has two working copies of the VHL gene. Patients with Von Hippel-Lindau syndrome generally carry a mutation in one copy of the VHL gene in all the cells of their body. Children with Von Hippel-Lindau syndrome are born and develop normally, but are at increased risk of developing benign and malignant tumors. These tumors are believed to develop because, over time, the second working copy of the VHL gene may become damaged within one or more cells. The loss of function of the second VHL gene copy leads to abnormal growth of the affected cells, increasing their chance to become cancerous.

How is Von Hippel-Lindau syndrome inherited?

Approximately 80 percent of patients with Von Hippel-Lindau syndrome inherit an altered copy of the VHL gene from a parent who also has Von Hippel-Lindau syndrome.

In the remaining 20 percent of patients, Von Hippel-Lindau syndrome results from the development of a “new” mutation in the VHL gene in one of the father’s sperm, mother’s eggs, or in a cell of the developing fetus. In the latter scenario, the affected individuals will be the first ones in their family to carry this genetic change. Individuals who carry an alteration in one copy of the VHL gene in all the cells of their body have a 50 percent chance of passing this same alteration onto each of his or her children. Children who inherit the altered gene copy will have Von Hippel-Lindau syndrome and will therefore be at risk of developing the features associated with this disease.

Genetic mosaicism in Von Hippel-Lindau syndrome

In about 5 percent of cases, an individual is a genetic “mosaic” for a VHL mutation. A person with VHL mosaicism has two different populations of cells that make up his body. One population contains two working copies of the VHL gene (these cells are normal) and a second population contains one working and one non-working VHL gene copy (these cells are abnormal).

The phenomenon of mosaicism may occur in the following way:

An individual inherits two working copies of the VHL gene, one from each parent via the egg and sperm at the time of conception. As the first cell of the fetus divides, each new cell will receive two working copies of the VHL gene.

After several cell divisions, a mutation in one copy of the VHL gene occurs in one cell of the developing fetus. This cell will now divide and create more cells like itself that carry one normal and one abnormal VHL gene copy. However, there still remains a population of normal cells that will continue to divide and produce cells with two working copies of VHL. Thus, as the baby grows, a proportion of the cells will contain two normal VHL gene copies and a second set of cells will be at risk to develop the features of Von Hippel-Lindau syndrome.

If some of the egg or sperm cells of a genetic mosaic carry the altered VHL gene copy, there is a chance that the mosaic individual can pass the VHL mutation onto future children. Because it is difficult to know which and how many cells of the body of a mosaic individual are affected, it is not possible to predict the exact risk to develop cancer or to pass an altered gene copy onto future children.

The clinical diagnosis of Von Hippel-Lindau syndrome relies on the presence of certain clinical findings. For an individual with no known family history of Von Hippel-Lindau syndrome, the occurrence of two or more characteristic lesions (a change in body tissue or an organ caused by disease) confirms a clinical diagnosis of the syndrome. Characteristic lesions may include:

Two or more hemangioblastomas of the brain, spinal cord or retina

A single hemangioblastoma and a kidney or pancreatic cyst or a renal cell carcinoma

Adrenal or extra-adrenal pheochromocytomas

An endolymphatic sac tumor

Papillary cystadenomas of the epididymis or broad ligament

Neuroendocrine tumors of the pancreas

For an individual with a positive family history of Von Hippel-Lindau syndrome, a clinical diagnosis of the syndrome is established by the presence of one or more of the following:

Retinal hemangioblastoma

Spinal or cerebellar hemangioblastoma

Pheochromocytoma

Multiple pancreatic cysts

Epididymal or broad ligament cystadenomas

Multiple kidney cysts

Renal cell carcinoma before age 60

A detailed review of an individual’s medical and family history becomes important in diagnosing Von Hippel-Lindau syndrome. A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that indicates which members of the family have developed cancer, the types of cancer and the ages of onset, as well as the presence of any clinical manifestations, such as benign tumors. If the pattern of clinical features and/or cancers is suggestive of Von Hippel-Lindau syndrome, the physician or counselor may recommend genetic testing be performed.

Testing for Von Hippel-Lindau syndrome

In order to confirm on a molecular level that an individual has Von Hippel-Lindau syndrome, he or she can undergo genetic testing:

Generally, a sample of blood is obtained from an affected individual.

DNA is isolated from this sample, and the two copies of the VHL gene are analyzed using a variety of methods and compared to the normal reference sequence for the VHL gene.

If an alteration in one VHL gene copy is identified, the genetic counselor can examine whether the alteration has been previously reported in other individuals with Von Hippel-Lindau syndrome.

It is estimated that close to 100 percent of individuals carrying a clinical diagnosis of Von Hippel-Lindau syndrome will have a mutation involving VHL. Some individuals may be mosaic and not have a detectable alteration of VHL in their blood cells. Therefore, the failure to identify an alteration in the VHL gene does not exclude the clinical diagnosis of Von Hippel-Lindau syndrome.

VHL genetic test results can also provide important information for other family members. If a mutation responsible for Von Hippel-Lindau syndrome is identified, at-risk relatives (first- or second-degree relatives) can be tested for the same genetic alteration. Almost every individual with a mutated VHL gene displays symptoms of Von Hippel-Lindau syndrome by age 65.

A person with Von Hippel-Lindau syndrome who does not wish to pass this disease onto future children has several options, including:

Prenatal diagnosis — DNA is obtained from the cells of the embryo through chorionic villus sampling (CVS) or amniocentesis. The DNA is analyzed for alterations in the VHL gene.

Preimplantation genetic diagnosis (PGD) — For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the VHL gene would be implanted.

Before one can proceed with prenatal testing or PGD, a VHL mutation must be identified in a parent with Von Hippel-Lindau syndrome. Using either method, a parent can work with a genetic counselor and/or physician to decide whether to carry the pregnancy to term or to end the pregnancy.

Individuals with an altered VHL gene are at increased risk to develop tumors in areas of the body that contain blood vessels. Most commonly, Von Hippel-Lindau patients develop tumors in the brain, retina, spinal cord, inner ear, and pancreas. Often, these tumors must be removed to prevent medical problems, but they are usually benign (non-cancerous).

About 15 percent of patients with Von Hippel-Lindau syndrome develop neuroendocrine tumors of the pancreas, which behave like cancers. Individuals with Von Hippel-Lindau syndrome are also at a high risk for renal cell carcinoma (malignant kidney cancer) which occurs in 40 percent of affected individuals. Pheochromocytomas are usually benign, but malignant behavior has been documented.

Occurrence and age of onset in VHL syndrome

CNS

Age at diagnosis

Most common ages at diagnosis

Frequency in patients

Retinal hemangioblastomas

0-68 years

12-25 years

25-60 percent

Endolymphatic sac tumors

1-50 years

16-28 years

11-16 percent

Cerebellar hemangioblastomas

9-78 years

18-25 years

44-72 percent

Brainstem hemangioblastomas

12-46 years

24-35 years

10-25 percent

Spinal cord hemangioblastomas

12-66 years

24-35 years

13-50 percent

Viscera

Renal cell carcinoma or cysts

16-67 years

25-50 years

25-60 percent

Pheochromocytomas

4-58 years

12-25 years

10-20 percent*

Pancreatic tumor or cyst

5-70 years

24-35 years

35-70 percent

Epididymal cystadenomas

17-43 years

14-40 years

25-60 percent (males)

APMO or broad ligament cystadenoma

16-46 years

16-46 years

Estimated 10 percent(females)

*Compiled from a survey of papers from 1976-2004, including data from the VHL Family Alliance. Frequency of pheochromocytoma varies widely depending on genotype."VHLFA Handbook." VHL Family Alliance. Last revised: 01/2005

Regardless of whether an at-risk individual decides to pursue genetic testing, he or she should be regularly monitored for the development of benign and malignant tumors associated with Von Hippel-Lindau syndrome.

While many of the tumors associated with Von Hippel-Lindau are benign, they should be followed closely or treated as their growth can cause other problems. For example, retinal hemangioblastomas can lead to loss of vision and pheochromocytomas can cause high blood pressure. Regular screening and appropriate management has been shown to reduce mortality and morbidity from this condition.

It is important for patients with Von Hippel-Lindau syndrome to be screened regularly for these issues:

Yearly blood pressure monitoring and measurement of plasma metanephrines beginning at age 5 (for individuals with a strong family history of pheochromocytoma).

Yearly ophthalmologic screening starting before age 5 to rule out the presence of retinal hemangioblastomas. If there is evidence of a hemangioblastoma, the frequency of screenings should be increased to every six months.

Yearly MRI evaluation of the abdomen and pelvis starting at age 8-11 depending upon an increased or decreased risk for pheochromocytoma as determined by the specific VHL mutation in the individual.

Audiologic assessment for individuals with a recognized hearing problem that could be the result of an endolymphatic sac tumor. Further radiologic testing should be done if abnormalities are found.

Complete physical examination annually.

Annual MRI of brain and spine at onset of puberty (about age 11), and before and after (but not during) pregnancy.

It is important to note that management of tumors differ depending on whether an individual develops a tumor as a result of having Von Hippel-Lindau syndrome or develops a sporadic tumor. An individual with Von Hippel-Lindau syndrome who develops a tumor should consult a physician with expertise in the management of this condition.

Adults and older children and adolescents should avoid the use of tobacco products, which increase the risk for kidney cancer.